Immediate/delayed drug delivery

ABSTRACT

In one aspect, the present invention is concerned with a treatment where it is desired that an active agent is designed to be released immediately following administration and again at a time point some time after administration of the active agent. The present invention is particularly suited to administering an agent which may be released before sleep and while a subject is sleeping. As well as treating certain conditions by a particular regime, the invention also provides novel formulations for an immediate, followed by a delayed release of drug.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a United States Application under 35 U.S.C. 371claiming benefit of PCT Application No. PCT/GB2011/000314, filed on Mar.4, 2011, which claims the benefit of GB 1003731.5, filed on Mar. 5,2010, the contents of each of which are incorporated herein byreference.

FIELD OF INVENTION

In one aspect, the present invention is concerned with a treatment whereit is desired that an active agent is designed to be releasedimmediately following administration and again at a time point some timeafter administration of the active agent. The present invention isparticularly suited to administering an agent which may be releasedbefore sleep and whilst a subject is sleeping. As well as treatingcertain conditions by a particular regime, the invention also providesnovel formulations for an immediate, followed by a delayed release ofdrug.

BACKGROUND TO THE INVENTION

Time-dependent release mechanisms of drugs have been described in theliterature for tablet, pellet and capsule formulation utilising a widerange of physicochemical and physicomechanical strategies. The commonfeature of all such formulations is that they are activated by contactwith fluids following ingestion by the patient and the drug will bereleased at the predetermined time after administration. Only after theformulations come into contact with gastric fluids does the ‘clock’start.

Drug release subsequently takes place at a predicted time, although itwill be appreciated that since the dosage unit will be travellingthrough the GI tract during the lag period, drug release willnecessarily be at some unknown GI tract site. Using such formulationstrategies, it will be possible to design delivery systems capable ofreleasing drugs according to chronotherapeutic principles and targetingrelease to the circadian rhythm of disease states (Stevens H N E,Chronopharmaceutical Drug Delivery. J Pharm Pharmac, 50 (s) 5 (1998))

However, many of the formulations in the art rely on complex structureswhich can add to the cost of the manufacture of the drug and/or can besubject to malfunction leading to incorrect/inappropriate administrationof the drug.

Diclofenac is a non-steroidal anti-inflammatory drug (NSAID) which istaken to reduce inflammation and as an analgesic reducing pain inconditions such as arthritis or acute injury. It can also be used totreat menstrual pain and dysmenorrhea.

Many diclofenac formulations to be taken orally comprise an entericcoating, which minimises direct contact between the drug and the gastricmucosa. It is known that diclofenac is poorly soluble in the stomach dueto the acid pH, but more soluble in the alkaline pH of the duodenum. Inthis manner many such formulations are generally designed to delayrelease until the formulation passes through the stomach.

U.S. Pat. No. 6,312,724 describes a sustained release formulationcomprising diclofenac.

It is amongst the objects of the present invention to obviate and/ormitigate at least one of the aforementioned disadvantages.

It is amongst the objects of the present invention to provide aformulation which may be easily and/or cheaply manufactured and whichallows for an active agent to be administered immediately and followinga period of delay following administration.

SUMMARY OF INVENTION

The present inventors recognised a need to be able to administer, forexample, a pharmaceutically active agent to a subject in a manner suchthat an immediate and a delayed release of the pharmaceutically activeingredient could be achieved. Although this may have been possible usingprior device/methods known in the art, many such devices/methods werehighly complex and there is distinct advantage in providing a simplerpress-coated tablet formulation.

One particularly preferred embodiment relates to treating subjects witharthritis or acute pain who may suffer pain before going to bed andwould also suffer pain/inflammation on waking. In a preferred embodimenttherefore, the formulations of the present invention are for alleviatingpain due to, for example, arthritis or acute injury. Such formulationstherefore comprise a pharmaceutically active agent for alleviatingpain/inflammation associated with arthritis or other conditions.Typically this may be a NSAID, such as diclofenac.

Thus, in a first aspect, the present invention provides a NSAID agentsuch as diclofenac, formulated as a component of a press-coated tabletfor alleviating pain and/or inflammation, wherein the tablet is intendedto be administered immediately prior to a subject going to sleep (i.e.when a subject goes to bed at night for a prolonged period of sleep,such as 6-10 hours and hence is distinguished over shorter sleepingperiods) and wherein a portion of the NSAID is initially to be releasedimmediately following administration and a further portion is releasedfollowing a period of delay after administration.

In a further aspect there is provided a method of alleviating painand/or inflammation such as associated with arthritis, the methodcomprising administering a press-coated tablet comprising an NSAID(s),such as diclofenac to a subject, immediately before the subject intendssleeping, wherein the formulation releases an NSAID immediatelyfollowing administration and further releases an NSAID following aperiod of delay after administration of the tablet.

It is to be appreciated that said NSAIDs may be in respect of the samedrug, or different drugs. Thus, for example, the first portion mayrelease a first NSAID and the second portion may release a different orthe same NSAID.

The immediate release of the active agent may be realised by way of atop-coating layer comprising an amount of the active agent together withone or more excipients therefore.

By “immediately” is understood to mean that at least 70-90%, such as 80%of the active agent in the top layer or portion of the press-coatedtablet which is formulated for immediate release is released withinabout 5-45 mins, such as 10-30 mins following administration and thefurther portion is released after a period of delay which is typicallyfrom 3-8 hours following administration.

Typically delayed release of the active agent is achieved by providing apress-coated tablet comprising a delayed release layer surrounding acore comprising the active agent. The delayed release layer may comprisea wax and LH-32.

In a further aspect, the present invention provides a press-coatedtablet formulation for an immediate, followed by a delayed release of anactive agent, the tablet comprising

(a) a core comprising an active agent together with an excipient(s); and

(b) a delayed release layer surrounding the core and comprising a waxand LH-32 in a ratio of 40:60 to 60:40 w/w; wherein the delayed releaselayer substantially delays release of the active agent within the corefor between 3-8 hours after administration of the tablet by a subjectand thereafter a pulsed release of the active agent from the coreoccurs, such that substantially all (typically greater than 90%, 95%, oreven 99%) of the active agent in the core is released within 5-45 mins,such as 10-30 mins; and(c) a top-coating layer comprising a portion of an active agent togetherwith one or more excipients wherein a substantially immediate pulsedrelease of the active agent occurs following administration to thesubject of the tablet.Delayed Release is More Preferably for 4-7 Hours FollowingAdministration.

The active agents of the above aspect may be the same or different andinclude any active agent for which delayed followed by pulsed release isdesirable. In a preferred embodiment of the invention, the active agentis a pharmaceutically acceptable active agent and includespharmaceutical and veterinary active agents (often referred to asdrugs). In other embodiments, the active agent includes agrichemicalagents (such as fertilizers, herbicides, pesticides and fungicides),active agent used in the exterminating industry (such as toxins andpoisons), and active agents used in industrial manufacturing (such ascatalysts or catalytic quenchers).

Exemplary active agents for use in the pharmaceutical and veterinaryapplications of the invention include analgesics, anti-inflammatories,anesthetics, anticonvulsants, antidiabetic agents, antihistamines,anti-infectives, antineoplastics, antiparkinsonian agents, antirheumaticagents, appetite stimulants, appetite suppressants, blood modifiers,bone metabolism modifiers, cardiovascular agents, central nervous systemdepressants, central nervous system stimulants, decongestants, dopaminereceptor agonists, electrolytes, gastrointestinal agents,immunomodulators, muscle relaxants, narcotics, parasympathomimetics,sympathomimetics, sedatives, and hypnotics.

The press-coated tablets of the present invention may be used to treatone or more of the following conditions/disorders or diseases:

Central Nervous System disorders, e.g. Neurogenic pain, stroke,dementia, Alzheimer's disease, Parkinson's disease, neuronaldegeneration, meningitis, spinal cord injury, cerebral vasospasm,amyotrophic lateral sclerosis

Cardiovascular disease, hypertension, atherosclerosis, angina, arterialobstruction, peripheral arterial disease, myocardial pathology,Arrhythmia, Acute Myocardial Infarction, Angina, Cardiomyopathy,Congestive heart failure, Coronary artery disease (CAD), Carotid arterydisease, Endocarditis, Hypercholesterolemia, hyperlipidemia, Peripheralartery disease (PAD)Genitourinary Disorders; erectile dysfunction, urinary organ diseasesbenign prostatic hypertrophy (BPH), Renal tubular acidosis, diabeticnephropathy, glomerulonephritis, glomerulosclerosis, urinary tractinfection, faecal incontinenceOcular disease glaucoma, blephartitis, ocular hypertension, retinopathy,conjunctivitis, scleritis, retinitis, keratitis, corneal ulcer, iritis,Chorioretinal inflammation, macular edema, XerophthalmiaPulmonary disease asthma, pulmonary hypertension, acute respiratorydistress syndrome, COPD, emphysema, pneumonia, tuberculosis, bronchitis,Acute Bronchitis, Bronchiectasis, Bronchiolitis, BronchopulmonaryDysplasia, Byssinosis, Coccidioidomycosis (Cocci), Cystic Fibrosis,Influenza, Lung Cancer, MesotheliomaMetabolic diseases; Hypercalciuria, Hyperglycemia, Hyperinsulinemichypoglycemia, Hyperinsulinism, Hyperlysinuria, HypoglycemiaExocrine and Endocrine; Addison's disease, Hypoaldosteronism, cushing'ssyndrome, diabetes, Goitre, Hyperthyroidism, Hypothyroidism,Thyroiditis, pancreatitisHepatic disorders, Hepatitis, Non-alcoholic fatty liver disease,cirrhosis, hepatic cancer, Primary sclerosing cholangitis, primarybiliary cirrhosis, Budd-Chiari syndrome,Autoimmune and Inflammatory diseases, multiple sclerosis rheumatoidarthritis, psoriasis, diabetes, sarcoidosis, Addison's Disease, Alopeciaareata, Amyotrophic Lateral Sclerosis, Ankylosing Spondylitis,polyarticular Arthritis, Atopic allergy, topic Dermatitis, Autoimmunehepatitis, Celiac disease, Chagas disease, Coeliac Disease, Cogansyndrome, Crohns Disease, Cushing's Syndrome, Diabetes mellitus type 1,Endometriosis, Eosinophilic fasciitis, Fibromyalgia/Fibromyositis,Gastritis, Glomerulonephritis, Graves' disease. Guillain-Barre syndrome(GBS), Hashimoto's encephalitis, Hashimoto's thyroiditis, Haemoiyticanaemia, idiopathic inflammatory Demyelinating Diseases, Idiopathicpulmonary fibrosis, interstitial cystitis, Juvenile idiopathicarthritis, Juvenile rheumatoid arthritis, Kawasaki's Disease, Lichensclerosus, Lupus erythematosus, Meniere's disease, Myasthenia gravis,myositis, Narcolepsy, Pernicious anaemia, Perivenous encephalomyelitis,Polymyalgia rheumatica, Primary biliary cirrhosis, Psoriatic Arthritis,Reiter's syndrome, Rheumatoid fever, Sarcoidosis, Schizophrenia,Sjogren's syndrome, Spondyloarthropathy, Ulcerative ColitisMusculoskeletal disorders: osteoarthritis, osteoporosis, Osteonecrosis,Arthritis, Paget's Disease Bursitis, Costochondritis, TendonitisSkin disorders; Acne, alopecia, candidiasis, cellulitis, dermatitis,eczema, epidermolysis bullosa, erythrasma, herpes, erysipelas,Folliculitis, impetigo, ringworm, scabies, Tinea, TrichomycosisENT disorders; Otitis, sinusitis, laryngitis, pharyngitis, laryngitis,meniere's disease, labyrinthitis,Others: acute and chronic pain, viral infection, cancer, laryngitis,mastoiditis, myringitis, otitis media, rhinitis, sinusitis,Sialadenitis, Retropharyngeal Abscess, Tonsillopharyngitis,Gastro-Intestinal DisordersIrritable bowel syndrome (IBS) necrotizing entercolitis (NEC) non-ulcerdyspepsia, chronic intestinal pseudo-obstruction, functional dyspepsia,colonic pseudo-obstructioduodenogastric reflux, gastroesophageal refluxdisease, ileus inflammation, gastroparesis, heartburn,constipation—(e.g. constipation associated with use for medications suchas opioids), colorectal cancer, colonic polyps, diverticulitis,colorectal cancer, Barretts Esophagus, Bleeding in the Digestive Tract,Celiac Disease, Colon Polyps, Constipation, Crohns DiseaseACyclicVomiting Syndrome, Delayed Gastric Emptying (Gastroparesis), Diarrhea,Diverticulosis, Duodenal Ulcers, Fecal Incontinence, Gallstones, Gas inthe Digestive Tract, Gastritis, Gastroesophageal Reflux Disease (GERD),Heartburn^Hiatal Hernia, Hemochromatosis, Hemorrhoids, Hiatal Hernia,Hirschsprung's Disease, Indigestion, Inguinal Hernia, LactoseIntolerance, Peptic Ulcers, Polyps, Porphyria, Primary BiliaryCirrhosis, Primary Sclerosing Cholangitis, Proctitis, Rapid GastricEmptying, Short Bowel Syndrome, Stomach Ulcers, Ulcerative Colitis,Uicers, whippies DiseaseSaid Active Agent or Agents May be Selected from the Following:Gastro DrugsAntacids—aluminium hydroxide, magnesium carbonate, magnesiumtrisilicate, hydrotalcite, simeticonealginates,Antispasmodics—atropine sulphate, dicycloverine hydrochloride, hyoscinebutylbromine, propantheline bromide, alverine citrate, mebeverinehydrochloride,Motility stimulants—metoclorpramide, domperidoneH2-Receptor antagonists—Cimetidine, famotidinenizatidine, ranitidineAntimuscarinics—pirenzepineChelates—Tripotassium dicitratbismuthate, sucralfate,Prostaglandin analogues—misoprostolAminosalicylates—balsazide sodium, mesalazine, olsalazine,sulphasalazineCorticosteroids—beclometasone dipropionate, budenoside, hydrocortisone,prednisolone,Affecting immune response—ciclosporin, mercaptopurine, methotrexate,adalimumab, infliximabStimulant Laxatives—bisacodyl, dantron, docusate, sodium picosulfate,Drugs affecting biliary composition and flow—ursodeoxycholic acidBile acids sequestrants—colestyramine, Oxyphencyclimine, Camylofin,Mebeverine, Trimebutine, Rociverine, Dicycloverine, Dihexyverine,Difemerine,Piperidolate Benzilone, Mepenzolate, Pipenzolate, Glycopyrronium,Oxyphenonium, Penthienate, Methantheline, Propantheline, Otiloniumbromide, Tridihexethyl, Isopropamide, Hexocyclium, Poldine, Bevonium,Diphemanil, Tiemonium iodide, Prifinium bromide, Timepidium bromide,Fenpiverinium Papaverine, Drotaverine, Moxaverine 5-HT3 antagonists(Alosetron, Cilansetron), 5-HT4 agonists (Mosapride, Prucaiopride,Tegaserod) Fenpiprane, Diisopromine, Chiorbenzoxamine, Pinaverium,Fenoverine, Idanpramine, Proxazole, Alverine, Trepibutone,Isometheptene, Caroverine, Phloroglucinol, Silicones,Trimethyldiphenylpropylamine Atropine, Hyoscyamine Scopolamine(Butylscopolamine, Methylscopolamine), Methylatropine, Fentonium,Cimetropium bromide primarily dopamine antagonists(Metoclopramide/Bromopride, Clebopride, Domperidone, Alizapride), 5-HT4agonists (Cinitapride, Cisapride),Proton pump inhibitors Omeprazole, lansoprazole, pantoprazole,esomeprazole, rabeprazole sodium,opioids and opiod receptor antagonists—e.g. codeine, morphine,loperamide, diphenoxylate, methylnaltrexone bromideAnalgesic Acetaminophen Diclofenac Diflunisal Etodolac FenoprofenFlurbiprofen Ibuprofen Indomethacin Ketoprofen Ketorolac MeclofenamateMefenamic Acid Meloxicam Nabumetone Naproxen Oxaprozin PhenylbutazonePiroxicam Sulindac Tolmetin Celecoxib Buprenorphine Butorphanol CodeineHydrocodone Hydromorphone Levorphanol Meperidine Methadone MorphineNalbuphine Oxycodone Oxymorphone Pentazocine, Propoxyphene TramadolcodeineSleep drugs Hypnotics—Nitrazepam, Flurazepam, Loprazolam, Lormetazepam,Temazepam, Zaleplon, Zolpidem, Zopiclone, Chloral Hydrate, Triclofos,Clomethiazole, Quazepam, triazolam Estazolam Clonazepam, Alprazolam,Eszopiclone, Rozerem, Trazodone, Amitriptyline Doxepin, Benzodiazepinedrugs, melatonin, diphenhydramine and herbal remedies such as ValerianCardiovascular MedicinesCardiac glycosides—Digoxin, digitoxin,Phosphodiesterase Inhibitors—enoximone, milrinoneThiazides and related diuretics—bendroflumethiazide, chlortalidone,cyclopenthiazide, inapamide, metolazone, xipamideDiuretics—furosemide, bumetanide, torasemide,Potassium sparing diuretics and aldosterone antagonists—amiloridehydrochloride, triamterene, weplerenone, spironolactone,Osmotic diuretics—mannitolDrugs for arrhythmias—adenosine, amiodarone hydrochloride, disopyramide,flecainide acetate, propafenone hydrochloride, lidocaine hydrochloride,Beta adrenoreceptor blocking drugs—propanalol, atenolol, acebutolol,bisprolol fumarate, carvedilol, celiprolol, esmolol, lebatolol,metoprolol tartrate, nadolol, nebivolol, oxprenolol, pindolol, solatol,timolol,Hypertension—ambrisentan, bosentan, diazoxide, hydralazine, iloprost,minoxidil, sildenafil, sitaxentan, sodium nitroprusside, clonidine,methyldopa, moxonidine, guanethidine monosulphate, doxazosin, indoramin,prazosin, terazosin, phenoxybenzamine, phentolamine mesilate,Drugs affecting the renin-angiotensin system—Captropril, Cilazapril,Enalapril Maleate, Fosinopril, Imidapril, Lisinopril, Moexipril,Perindopril Erbumine, Quinapril, Ramipril, Trandolapril, CandesartanCilexetil, Eprosartan, Irbesartan, Losartan, Olmesartan Medoxomil,Telmisartan, Valsartan, Aliskiren.Nitrates, calcium channel Blockers and antianginal drugs—Glyceryltrinitrate, Isosorbide Dinitrate, Isosorbide Mononitrate, Amlodipine,Diltiazem, Felodipine, Isradipine, Lacidipine, Lercanidipine,Nicardipine, Nifedipine, Nimodipine, Verapamil, Ivabradine, Nicorandil,Ranolazine,Peripheral Vasodilators and related drugs—Cilostazol, InositolNicotinate, Moxisylyte, Naftidrofuryl Oxalate, Pentoxifylline,Sympathomimetics—Dopamine, Dopexamine, Ephedrine, Metaraminol,Noradrenaline Acid Tartrate, Norephidrine Bitartrate, Phenylephidrine,Anticoagulants and Protamine—Heparin, Bemiparin, Dalteparin, Enoxaparin,Tinzaparin, Danaparoid, Bivalirudin, Lepirudin, Epoprostenol,Fondaprinux, Warfarin, Acenocoumarol, Phenindione, Dabigatran Etexilate,Rivaroxaban, Protamine Sulphate,Antiplatelet Drugs—Abciximab, Asprin, Clopidogrel, Dipyridamole,Eptifibatide, Prasugrel, Tirofiban,Fibrinolytic and antifibrinolytic Drugs—Alteplase, Reteplase,Streptokinase, Tenecteplase, Urokinase, Etamsylate, Tranexamic Acid,Lipid Regulating Drugs—Atorvastatin, Fluvastatin, Pravastatin,Rosuvastatin, Simvastatin, Colesevam, Colestyramine, Colestipol,Ezetimibe, Bezafibrate, Ciprofibrate, Fenofibrate, Gemfibrozyl, Acipmox,Nictotinic Acid, Omega three fatty acid compounds, Ethanolamine Oleate,Sodium Tetradecyl Suphate.CNS Drugs—Benperidol, Chlorpromazine, Flupentixol, Haloperidol,Levomepromazine, Pericyazine, Perphenazine, Pimozide, Prochlorperazine,Promazine, Sulpiride, Trifluoperazine, Zuclopenthixol, Amisulpride,Aripiprazole, Clozapine, Olanzapine, Paliperidone, Quetiapine,Riperidone, Sertindole, Zotepine, Flupentixol, Fluphenazine, OlanzapineEmbonate, Pipotiazine Palmitate, Risperidone, Zuclopenthixol Decanoate,Carbamazepine, Valproate, Valproic acid, Lithium Carbonate, LithiumCitrate, Amitriptyline, Clomipramine, Dosulepin, Imipramine,Lofepramine, Nortriptyline, Trimipramine, mianserin, Trazodone,Phenelzine, Isocarboxazid, Tranylcypromine, Moclobemide, Citalopram,Escitalopram, Fluoxetine, Fluvoxamine, Paroxetine, Sertraline,Agomelatine, Duloxetine, Flupentixol, Mirtazapine, Reboxetine,Trytophan, Venflaxine, Atomoxetine, Dexametamine, Methylphenidate,Modafinil, Eslicarbazepine, Ocarbazepene, Ethosuximide, Gabapentin,Pregabalin, Lacosamide, Lamotrigine, Levetiracetam, Phenobarbital,Primidone, Phenytoin, Rufinamide, Tiagabine, Topiramate, Vigabatrin,Zonisamide, ropinirole, Rotigotine, Co-Beneldopa, Levodopa,Co-Careldopa, Rasagiline, Selegiline, Entacapone, Tolcapone, Amantidine,Orphenadrine, Procyclidine, Trihexyphenidyl, Haloperidol, Piracetam,Riluzole, Tetrabenazine, Acamprosate, Disulfiram, Bupropion,Vareniciline, Buprenorphine, Lofexidine, Donepezil, Galantamine,Memantine, Rivastigimine.Anti-Infectives—Benzylpenicillin, Phenoxymethylpenicillin,Flucloxacillin, Temocillin, Amoxicillin, Ampicillin, Co-Amoxiclav,Co-Fluampicil, Piperacillin, Ticarcillin, Pivmecillinam, Cephalosporins,Cefaclor, Cefadroxil, Cefalexin, Cefixime, Cefotaxime, Cefradine,Ceftazidime, Cefuroxime, Ertapenem, Imipenem, Meropenem, Aztreonam,Tetracycline, Demeclocycline, Doxocycline, Lymecycline, Minocycline,Oxytetracycline, Tigecycline, Gentamicin, Amikacin, Neomycin,Tobramycin, Erythromycin, Azithromycin, Clarithromycin, Telithromycin,Clindamycin, Chloramphenicol, Fusidic Acid, Vancomycin, Teicoplanin,Daptomycin, Linezolid, Quinupristin, Colistin, Co-Trimoxazole,Sulpadiazine, Trimethoprim Capreomycin, Cycloserine, Ethambutol,Isoniazid, Pyrazinamide, Rifabutin, Rifampicin, Streptomycin, Dapsone,Clofazimine, Metronidazole, Tinidazole, Ciproflaxacin, Levoflaxacin,Moxifloxacin, Nalidixic Acid, Nortlaxine, Orliaxacin, Nitrofurantoin,Methenamine Hippurate, Amphotericin, Anidulafungin, Caspofungin,Fluconazole, Flucytosine, Griseofluvin, ltraconzole, Ketoconazole,Micafungin, Nystatin, Posaconazole, Terbinafine, Voriconazole, Abacavir,Didanosine, Emtricitabine, Lamivudine, Stavudine, Tenofovir Disoproxil,Zidovudine, Atazanavir, Darunavir, Fosamprenavir, Indinavir, Lopinair,Nelfinavir, Ritonavir, Saquinavir, Tipranavir, Efavirenz, Etravirine,Nevarapine, Enfuvirtide, Maraviroc, Raltegravir, Aciclovir, Famciclovir,Inosine Pranobex, Valaciclovir, Cidofovir, Gangciclovir, Foscarnet,Valgangciclovir, Adefovir Dipivoxil, Entecavir, Telbivudine, Amantadine,Oseltamivir, Zanamivir, Palivizumab, Ribavirin, Artemether, Chloroquine,MefloquinePrimaquine, Proguanil, Pyrimethamine, Quinine, Doxycyclin,Diloxanide Furoate, Metronidaziole, Tinidazole, MepacrineSodiumStibogluconate, Atovaquone, Pentamidine Isetionate, Mebendazole,Piperazine,Other:Benztropine, procyclidine, biperiden, Amantadine, Bromocriptine,Pergolide, Entacapone, Tolcapone, Selegeline, Pramipexole, budesonide,formoterol, quetiapine fumarate, olanzapine, pioglitazone, montelukast,Zoledromic Acid, valsartan, latanoprost, Irbesartan, Clopidogrel,Atomoxetine, Dexamfetamine, Methylphenidate, Modafinil, Bleomycin,Dactinomycin, Daunorubicin, Idarubicin, Mitomycin, Mitoxantrone,Azacitidine, Capecitabine, Cladribine, Clofarabine, Cytarabine,Fludarabine, Flourouracil, Gemcitabine, mercaptopurine, methotrexate,Nelarabine, Pemetrexed, Raltitrexed, Thioguanine, Apomorphine,Betamethasone, Cortisone, Deflazacort, Dexamethosone, Hydrocortisone,Methylprednisolone, Prednisolone, Triamcinolone, Ciclosporine,Sirolimus, Tacrolimus, Interferon Alpha, Interferon Beta.In a particularly preferred embodiment the active agent is designed totreat arthritis and/or acute pain and as such the active agent ispreferably an NSAID, such as diclofenac.

The term “active agent” is understood to include solvates (includinghydrates) of the free compound or salt, crystalline and non-crystallineforms, as well as various polymorphs. For example, the active agent caninclude all optical isomers of the compounds and all pharmaceuticallyacceptable salts thereof either alone or in combination threo isomerscan be indicated as “threo” and the combined erythro isomers as“erythro”.

In accordance with the invention, formulations are provided which are tobe taken by a subject and which initially administer a portion of theactive agent when the subject first takes the formulation and moreoverat a later time point a further portion of the agent is administered tothe subject. Preferably the immediate and/or delayed administration maybe by way of a pulsed dose, where said portion of active agent issubstantially delivered within about 5-45 mins, such as 10-30 mins.

The present inventors identified the need to be able to administer apain relieving/anti-inflammatory drug to a subject before the subjectwent to bed, but recognised that often subjects feel pain immediatelyupon waking and if they were to take pain relief once awake, there wouldbe a period of time when they suffered pain. The present inventorstherefore developed formulations which as well as deliveringpain/anti-inflammatory relief prior to sleep, also deliverpain/anti-inflammatory relief shortly before waking and hence serve toimprove pain management by the subject.

LH-32 is a particular type of low substituted hydroxypropyl cellulose(L-HPC) and may be obtained from Shin-Etsu Chemical Co., Ltd., Tokyo,Japan. L-HPCs are insoluble in water and comprise a glucose backbonewhich is substituted to a minimal extent by hydroxypropyl groups. LH-32is micronised, with a mean particle diameter of 20 Qm LH-32 has amolecular weight of around 115,000 and a hydroxypropyl cellulose contentof around 8%.

The wax may be any suitable wax such as beeswax, carnuba wax,microcrystalline wax, hydrogenated castor oil. A particularly preferredwax is a glyceryl ester, such as glycerol behenate.

In a preferred formulation of the present invention as defined hereinabove, the wax and LH-32 are present in a ratio of 40:60 to 60:40 w/w.More preferably the ratio is 45:55 to 55:45 w/w, or 50:50 w/w. Theskilled addressee will appreciate that with appropriate variation of theratio, the delay in drug release can be tailored for a particularapplication. For example, a 50:50 w/w ratio of glycerol behenate as awax, with LH-32 employed as a delayed release layer in accordance withthe present invention, is observed to provide a delayed release ofapproximately 6 hours. However, the same ratio with LH-21 as the L-HPCprovides a delay in release of oniy 2 hours. Thus with appropriatecontrol of the ratio of wax to L-HPC and the type of wax/L-HPC, it ispossible to control the time delay in release of the active agent, froma press-coated tablet comprising a delayed release layer surrounding acore comprising the active agent.

The delayed release layer surrounding the core may also comprise anamount of an active agent or agents, which may be the same or differentto the active agent in the core and/or top layer, and which is designedto be released during dissolution/disintegration of the delayed releaselayer.

The top layer comprises an active ingredient for immediate release andgenerally comprises one or more excipients, such as a sugar and/or anL-HPC.

The subject to be treated is an animal, e.g. a mammal, especially ahuman.

The amount of active agent to be administered will be sufficient to betherapeutic or prophylactic. By therapeutic or prophylactic is meant onecapable of achieving the desired response, and will be adjudged,typically, by a medical practitioner. The amount required will dependupon one or more of at least the active compound(s) concerned, thepatient, the condition it is desired to treat or prevent and theformulation. However, it is likely to be in the order of from 1 μg to 1g of compound per kg of body weight of the patient being treated.

Different dosing regimes may likewise be administered, again typicallyat the discretion of the medical practitioner. The formulation of thepresent invention may allow for at least daily administration althoughregimes where the compound(s) is (or are) administered moreinfrequently, e.g. every other day, weekly or fortnightly, for example,are also embraced by the present invention.

By treatment is meant herein at least an amelioration of a conditionsuffered by a patient; the treatment need not be curative (i.e.resulting in obviation of the condition). Analogously references hereinto prevention or prophylaxis herein do not indicate or require completeprevention of a condition; its manifestation may instead be reduced ordelayed via prophylaxis or prevention according to the presentinvention.

For use according to the present invention, the compounds orphysiologically acceptable salt, solvate, ester or other physiologicallyacceptable functional derivative thereof described herein are presentedin a press-coated tablet form comprising the compound or physiologicallyacceptable salt, ester or other physiologically functional derivativethereof, together with one or more pharmaceutically acceptableexcipients therefore and optionally other therapeutic and/orprophylactic ingredients. Any excipients are acceptable in the sense ofbeing compatible with the other ingredients of the formulation and notdeleterious to the recipient thereof.

The tablets of the present invention may be prepared using reagents andtechniques readily available in the art and/or exemplary methods asdescribed herein.

The tablets include those suitable for oral, rectal or vaginaladministration. The tablets may, where appropriate, be convenientlypresented in discrete dosage units and may be prepared by any of themethods well known in the art of pharmacy.

Compressed tablets may be prepared by compressing in a suitable machinean active compound in a free-flowing form such as a powder or granulesoptionally mixed with a binder, lubricant, inert diluent, lubricatingagent, surface-active agent or dispersing agent, together with thematerials for forming the delayed release layer. The tablets alsocomprise a top-coat comprising a portion of the active agent forimmediate release.

Tablets suitable for rectal administration are most preferably presentedas unit dose suppositories. Suitable carriers include cocoa butter andother materials commonly used in the art. The suppositories may beconveniently formed by admixture of a tablet with the softened or meltedcarrier(s) followed by chilling and shaping in moulds.

The tablets of the present invention may be prepared usingpharmaceutical processes namely by direct compression or by granulationprocessing and final tableting. The process may comprise the steps ofinitially forming a core comprising the active agent and subsequentlysurrounding core with the delayed release layer and a further top layer.The core may be formed by dispersing one or more active agents with oneor more excipients, such as a sugar, microcrystalline cellulose talc,dicalcium phosphate and the like.

The delayed release layer may be formed by melting the wax component andsubsequently admixing the other components including the LH-32. Themixture may then be allowed to cool and solidify before being groundand/or forced through a sieve, in order to achieve granules of the sizerange 500 Qm-1 mm. The core may then be coated with the delayed releaselayer material by direct compression. Typically the core is sandwichedbetween top and bottom layers of the delayed release material and hencecompletely surrounds the core.

At the same time, the top-coating layer may be press-coated on top ofthe delayed release layer. The top-coating may be formed by blendingtogether the active agents and one or more excipients, such as a sugar(e.g. lactose) and a L-HPC, such as LH-21.

The tableting for the formulation of tablets may be conducted using anapparatus ordinarily employed for the formation or granulation oftablets. Examples may include single-punch tableting machine, rotarytableting machine and tableting tester.

Tableting is conducted usually under a pressure of 50 to 300 MPa,preferably 80 to 200 MPa. At a pressure less than 50 MPa, the resultingtablet may have insufficient hardness, which disturbs easily handling,while pressures exceeding 300 MPa may serve to cause a delay indisintegration.

The core, delayed release layer and/or top-coating layer may include afiller, such as a water insoluble filler, water soluble filler, andmixtures thereof. The water insoluble filler, may be a calcium salt ortalc. Exemplary water soluble fillers such as water soluble sugars andsugar alcohols, preferably lactose, glucose, fructose, mannose,galactose, the corresponding sugar alcohols and other sugar alcohols,such as mannitol, sorbitol, and xylitol.

The filler in one of the layers can be the same or different as thefiller in another layer, if any. For example, the core composition caninclude a water-soluble filler while the top-coat composition caninclude a water insoluble filler.

Other excipients can also be present in the core delayed release layerand/or top-coating layer, including lubricants (such as talc andmagnesium stearate), glidants (such as fumed or colloidal silica), pHmodifiers (such as acids, bases and buffer systems), andpharmaceutically useful processing aids. It will be appreciated thatsuch other excipients may be the same or different in the core anddelayed release layer, if any.

In a preferred embodiment of the invention, the core components (activeagent and optional excipients) are blended together and compressed intosuitable cores. The blending can take place in any order of addition.Preferably, the cores are blended by starting with the smallest volumecomponent and then successively adding the larger volume components.

DETAILED DESCRIPTION

The present invention will now be further described by way of exampleand with reference to the figures which show:

FIG. 1 shows the release profile of a tablet formulation comprising animmediate release top-coating and a delayed release layer of 50:50 w/wglycerol behenate: LH-32;

FIG. 2 shows the release profile of a tablet formulation comprising animmediate release top-coating and a delayed release layer of 50:50 w/wglycerol behenate: LH-21;

FIG. 3 shows Gamma Scintigraphy imaging of In-vivo release of controlledrelease Diclofenac formulation. Radiolabel was incorporated in thedelayed release layer only and so only the delayed release is beingvisualised; and

FIG. 4 shows the analysis of blood plasma levels of Diclofenac followingadministration of a controlled release formulation of Diclofenac, thereis a period of time between drug release and detection in blood plasmaas the drug is solubilised and absorbed by the body.

CLINICAL NEED

This formulation is designed to relieve night-time pain (e.g. inarthritic patients) by releasing an immediate burst of diclofenac andthen another after six hours.

Methods

Core Tablet Blend and Core Tablet Compression

(MW Diclofenac=296.2 and MW Diclofenac sodium=318.1)

(i) Diclofenac and excipients weighed into tared weigh boats and allexcept the magnesium stearate placed into an amber screw-top glass jarof sufficient volume (e.g. 125 ml) according to Table 1.

TABLE 1 API/Excipient Weight (g) Diclofenac sodium 5.4 Ac-di-sol 1.3Lactose 1.7 Magnesium stearate 0.6(ii) These API/excipients blended (in the glass jar) using the Turbulamixer for 1 minute.(iii) Magnesium stearate added and all blended for further 5 minutes 90mg of this blend comprises each core tablet. 90 mg weighed into a taredweigh boat.(iv) The 6.9 mm punch and die set used to compress 90 mg powder for 10seconds at 1 ton using the IR press.(v) Tablets stored in an amber glass screw-top jar until use.Granules (to Surround Core Tablet)(i) Glycerol behenate and LH-32 weighed into tared weigh boats accordingto Table 2:

TABLE 2 Excipient Weight (g) GB 10 LH-32 10(ii) GB placed in a glass beaker on a hot plate set at 100° C. Once theGB melted, LH-32 added gradually whilst stirring until a uniform mix isachieved.(iii) The mix stirred continuously until cooled to room temperature. Thegranules are left for at least 30 min at room temperature before thenext step.(iv) The cooled granules forced through a 1 mm sieve (using a spatulaand a brush) and collected on a 500μη sieve so that the granules usedare in the size range 500μη∩-1 mm.(v) Granules stored in amber glass screw-top jar until use.Top Layer Blend

Diclofenac and excipients are weighed into tared weigh boats and allplaced into an amber screw-top glass jar of sufficient volume (eg 125ml) according to Table 3.

TABLE 3 API/Excipient Weight (g) Diclofenac sodium 10.8 Lactose 8.6LH-21 8.6

The API/excipients blended (in the glass jar) using the Turbula mixerfor 15 minutes.

Formulation Compression

(i) A 13 mm die and matching flat-faced punches were used to compressthe formulation. For 6 tablets, 12×250 mg granules (to surround coretablet) are weighed into tared weigh boats.

(ii) 250 mg granules placed onto the lower punch, core tablet dropped onand centralised (centralising tool) before placing the other 250 mggranules on top.

(iii) For 6 tablets, 6×140 mg top layer blend weighed into tared weighboats.

(iv) 140 mg of the top layer blend added to the top granule layer.

(v) The formulation compressed at 5 ton for 3 minutes in a 13 mmdie/punch set.

Dissolution

Dissolution (n=3) performed in 900 ml sodium phosphate buffer (0.01 M,pH 7) at 37° C., with UV analysis at 248 nm.

Results

As can be seen in FIG. 1, a tablet is provided which provides an initialrelease of diclofenac, over about 10 minutes, followed by a delay ofabout 5.5. hours and a further release of diclofenac over about 30-40mins.

Supporting Data

This profile in FIG. 2 shows a dramatically shortened time betweenpulses of diclofenac e.g. with LH-21 instead, as compared to that withLH-32, thus rendering it inappropriate for the desired clinicalapplication.

Clinical Trial Protocol

Diclofenac 50 mg immediate-release with diclofenac 50 mg delayed-release(6 hour time-delay)

Diclofenac Extraction from Plasma Calibration and Calculation of %Recovery

Preliminary Preparation:

-   1. Preparation of 100 ml stock solution of 3M Orthophosphoric acid    (H3PO4. 98 g/mol)-   (i) Using an 85% solution (VWR).-   (ii) 3M=294 g/L, therefore 29.4 g in 100 ml.-   (iii) Take 34.6 ml of the 85% VWR solution and make up to 100 ml    with water in a volumetric flask.-   2. Preparation of 1 L stock solution of Hexane:IPA, 90:10.-   (i) Add 900 ml hexane and 100 ml IPA to a 1 L duran bottle. Wrap the    top with parafilm for storage.    3. Ketoprofen (internal standard) stock solution (1 mg/ml)-   (i) Weigh 100 mg into a weigh boat and transfer to a 100 ml    volumetric flask. Add 60 ml mobile phase and dissolve. Make up to    the 100 ml mark with mobile phase.-   4. Diclofenac stock solutions-   (i) Solution A: Weigh 100 mg diclofenac and make up to 100 ml with    water in a volumetric flask (1 mg/ml).-   (ii) Solution B: Take 10 ml from Solution A and make up to 100 ml    with water in a volumetric flask (100 μg/ml).-   (iii) Solution C: Take 10 μI of Solution A and make up to 1 ml with    water (1 pg/ml).    Preparing the Standard Series of Diclofenac Solutions:

Add the required volume of either stock solution B or C to a small vialand make up to 1 ml with water as shown in the following table.

Required Conc. Vol stock Vol H₂O In 100 μl Standard (μg/ml) sol. (μl)(μl) (ng) 1 0.25 250 (C) 750 25 2 0.5 500 (C) 500 50 3 1.0  10 (B) 990100 4 2.5  25 (B) 975 250 5 5.0  50 (B) 950 500 6 10 100 (B) 900 1000 720 200 (B) 800 2000 8 30 300 (B) 700 3000Extraction Procedure:

-   -   (i) Add 1 ml blank plasma to each of 8 plastic 15 ml centrifuge        tubes    -   (ii) Add 100 μI of the diclofenac stock solutions to each    -   (iii) Vortex for 1 min    -   (iv) Add 1 ml of 3M Orthophosphoric acid to each    -   (v) Add 5 ml of hexane:isopropyl alcohol, 90:10    -   (vi) Vortex for 3 min    -   (vii) Centrifuge at 2000 rpm for 3 min    -   (viii) Extract the top (solvent) layer and transfer to a clean        centrifuge tube    -   (ix) Evaporate the solvent to dryness under nitrogen    -   (x) Reconstitute residue in 100 μI mobile phase    -   (xi) Add 10 μI internal standard stock solution to each    -   (xii) Vortex    -   (xiii) Inject 50

The on column mass for each sample is as follows:

On column mass Sample (ng) 1 12.5 2 25 3 50 4 125 5 250 6 500 7 1000 81500

Clinical studies were carried out in Healthy male volunteers agedbetween 18-65 years inclusive with a body mass index (BMI) between 18.0and 29.9 kg/m². Subjects received a standard dinner comprising roastchicken with salad, low fat yoghurt and one cup of decaffeinated tea,coffee or juice 2 hours prior to dosing.

Gastrointestinal transit of the delayed-release tablets wascharacterised by inclusion of a radiolabel marker, technetium-99m(^(99m)Tc), complexed with diethylenetriaminepentaacetic acid (DTPA)which prevents absorption from the gastrointestinal tract. Theradiolabel is incorporated into the core tablet. Each tablet wasradiolabelled with 4 MBq 99mTc-DTPA and administered with 240 ml ofwater at bedtime.

Scintigraphic imaging was performed using a Siemens E-Cam gamma camerafitted with a low-energy high-resolution collimator. Subjects wereimaged in a standing position except during periods of sleep where thesubjects were imaged lying down. Anterior static acquisitions of25-second duration each were collected immediately after dosing thenevery 30 minutes until 3 hours post-dose then every 15 minutes untilcomplete release of radiolabel marker.

A 5 mL pre-dose blood sample was taken from each subject 15 minutesbefore dosing. Following dosing blood samples were taken. Every 15minutes until 2 hours post-dose then every 30 minutes until burstrelease observed by scintigraphy then every 15 minutes for 2 hours thenevery 30 minutes for 1 hour then hourly until end of study day (15 hourspost-dose). See FIG. 3.

Blood samples were centrifuged at 2000 g for 10 minutes and the plasmafraction removed and stored at −20° C. for subsequent analysis. See FIG.4.

The invention claimed is:
 1. A press-coated tablet formulation for animmediate, followed by a delayed release of an active agent, the tabletcomprising: (a) a core comprising an active agent together with anexcipient(s); and (b) a delayed release layer surrounding the core andcomprising a wax and a low substituted hydroxypropyl cellulose in aratio of 40:60 to 60:40 w/w; wherein the delayed release layersubstantially delays release of the active agent within the core forbetween 3-8 hours after administration of the tablet to a subject andthereafter a pulsed release of the active agent from the core occurs,such that at least 70% of the active agent in the core is releasedwithin 5-45 minutes and wherein the low substituted hydroxypropylcellulose is micronized with a mean particle diameter of 20 mm and has amolecular weight of 115,000 and a hydroxypropyl cellulose content of 8%;and (c) a top-coating layer comprising a portion of an active agenttogether with one or more excipients wherein a substantially immediatepulsed release of the active agent occurs following administration tothe subject of the tablet; wherein the active agent in the core and onthe top-coating layer is an NSAID.
 2. The press-coated tablet accordingto claim 1 further comprising an amount of an active agent, which is thesame or different to the active agent in the core and/or top-coatinglayer, in the delayed release layer.
 3. The press-coated tabletaccording to claim 1 wherein the wax is selected from the groupconsisting of beeswax, carnuba wax, microcrystalline wax, hydrogenatedcastor oil, and a glyceryl ester.
 4. The press-coated tablet accordingto claim 3 wherein the glyceryl ester is glycerol behenate.
 5. Thepress-coated tablet according to claim 1 wherein the wax and the lowsubstituted hydroxypropyl cellulose are present in a ratio of 45:55 to55:45 w/w.
 6. The press-coated tablet according to claim 5 wherein thewax and the low substituted hydroxypropyl cellulose are present in aratio of 50:50 w/w ratio and wherein the wax is glycerol behenate.
 7. Amethod of alleviating pain and/or inflammation, the method comprisingadministering a press-coated tablet according to claim
 1. 8. The methodaccording to claim 7 wherein the NSAID is diclofenac.
 9. The methodaccording to claim 7 wherein delayed release of the NSAID is achieved byproviding a press-coated tablet comprising a delayed release layersurrounding a core comprising the NSAID agent.
 10. The method accordingto claim 9 wherein the delayed release layer comprises a wax and a lowsubstituted hydroxypropyl cellulose, wherein the low substitutedhydroxpropyl cellulose is micronized with a mean particle diameter of 20mm and has a molecular weight of 115,000 and a hydroxypropyl cellulosecontent of 8%.
 11. The press-coated tablet according to claim 1, whereinthe active agent is diclofenac.
 12. A press-coated tablet formulationfor an immediate, followed by a delayed release of an NSAID activeagent, the tablet comprising: (a) a core comprising an active agenttogether with an excipient(s); and (b) a delayed release layersurrounding the core and comprising a wax and a low substitutedhydroxypropyl cellulose in a ratio of 40:60 to 60:40 w/w; wherein thedelayed release layer substantially delays release of the active agentwithin the core for between 3-8 hours, and thereafter a pulsed releaseof the active agent from the core occurs, such that at least 70% of theactive agent in the core is released within 5-45 minutes; wherein thelow substituted hydroxypropyl cellulose is micronized with a meanparticle diameter of 20 mm and has a molecular weight of 115,000 and ahydroxypropyl cellulose content of 8%; and (c) a top-coating layercomprising a portion of an active agent together with one or moreexcipients wherein a substantially immediate pulsed release of theactive agent occurs following administration to the subject of thetablet; wherein said release is measured in 900 ml of 0.01M sodiumphosphate buffer at pH 7, at 37° C. as determined by UV analysis at 248nm; wherein the active agent in the core and on the top-coating layer isan NSAID.
 13. The press-coated tablet according to claim 12 furthercomprising an amount of an active agent, which is the same or differentto the active agent in the core and/or top-coating layer, in the delayedrelease layer.